RNASET2 is required for ROS propagation during oxidative stress-mediated cell death
G Caputa1, S Zhao1, A E G Criado1
1Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
RNASET2 is a ubiquitously expressed acidic ribonuclease that has been implicated in diverse pathophysiological processes including tumorigeneis, vitiligo, asthenozoospermia, and neurodegeneration. Prior studies indicate that RNASET2 is induced in response to oxidative stress and that overexpression of RNASET2 sensitizes cells to reactive oxygen species (ROS)-induced cell death through a mechanism that is independent of catalytic activity. Herein, we report a loss-of-function genetic screen that identified RNASET2 as an essential gene for lipotoxic cell death. Haploinsufficiency of RNASET2 confers increased antioxidant capacity and generalized resistance to oxidative stress-mediated cell death in cultured cells. This function is critically dependent on catalytic activity. Furthermore, knockdown of RNASET2 in the Drosophila fat body confers increased survival in the setting of oxidative stress inducers. Together, these findings demonstrate that RNASET2 regulates antioxidant tone and is required for physiological ROS responses.
Insights
RNASET2 is crucial for cell death from fat overload and oxidative stress. Its catalytic activity is essential for regulating antioxidant capacity and responding to reactive oxygen species (ROS).
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- RNASET2 is an acidic ribonuclease linked to various diseases.
- Previous research showed RNASET2 is upregulated by oxidative stress and sensitizes cells to ROS-induced death, independent of its catalytic activity.
- Recent findings highlight RNASET2's role in lipotoxic cell death.
Purpose of the Study:
- To investigate the role of RNASET2 in lipotoxic cell death.
- To determine the mechanism by which RNASET2 influences cellular responses to oxidative stress.
- To explore the catalytic activity-dependent functions of RNASET2.
Main Methods:
- Loss-of-function genetic screen to identify genes essential for lipotoxic cell death.
- Cell culture experiments to assess RNASET2 haploinsufficiency effects on oxidative stress resistance.
- Drosophila melanogaster models to study RNASET2 function in vivo.
Main Results:
- RNASET2 was identified as essential for lipotoxic cell death.
- Haploinsufficiency of RNASET2 resulted in increased antioxidant capacity and resistance to oxidative stress-mediated cell death.
- This resistance was dependent on RNASET2's catalytic activity.
- Knockdown of RNASET2 in Drosophila fat body increased survival against oxidative stress inducers.
Conclusions:
- RNASET2 plays a critical role in regulating cellular antioxidant tone.
- The catalytic activity of RNASET2 is essential for its function in oxidative stress responses.
- RNASET2 is required for physiological responses to reactive oxygen species (ROS).
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